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PULMONARY
HYPERTENSION
   DR. ABHAY MANGE
PULMONARY CIRCULATION
 The pulmonary circulation is the vascular system that
    conducts blood from the right to left side of the heart
    through the lungs
   Pulmonary arteries are very thin walled and distensible.
   Pulmonary vascular resistance (PVR) is a measure of the
    impedance to flow in the pulmonary vasculature
   PVR Depends on pulmonary artery pressure ,left atrial
    pressure and the cardiac output
   Normal pulmonary artery pressure=25/8 mmHg
   Normal mean pulmonary artery pressure=15+/-3mmHg
INTRODUCTION
 Pulmonary hypertension (PH) is an abnormal
    elevation in pulmonary artery pressure
   It is a feature of advanced disease.
    The pulmonary artery pressure and pulmonary
    vascular resistance progressively rises, leading to
    right heart failure and death.
   Over the years, improvement in understanding the
    pathogenesis has resulted in the development of
    targeted approaches to the treatment of PH.
   Survival advantage has also been shown with some
    of the pharmacologic agents.
DEFINATIONS
 Pulmonary hypertension (PH) is haemodynamic
  and pathophysiological condition defined as
  mean pulmonary artery pressure > 25 mmHg at
  rest by Right heart Catheterization(RHC).

 Pulmonary arterial hypertension (PAH) is a clinical
  condition characterized by the presence of pre-
  capillary PH in absence of other causes of pre-
  capillary PH such as PH due to lung
  diseases, chronic thromboembolic PH, or other
  rare diseases
HISTORY
 E. Romberg, German doctor published description of
  autopsy, showed thickening of the pulmonary artery but
  no heart or lung disease.
 In 1951, 39 cases were reported by Dr. D.T. Dresdale in
  the United States.
 Between 1967 and 1973, a 10-fold increase in
  unexplained PH was reported in central Europe.
 The rise was subsequently traced to Aminorex
  fumarate, an amphetamine-like drug introduced in
  Europe in 1965 to control appetite.
CLASSIFICATION OF
    PULMONARY HYPERTENSION

 First version was proposed in 1973 at the first
  international conference on PPH by WHO.
 Second and third world meetings on PAH in 1998 and
  2003, respectively.
 Fourth World meet on PH held in 2008 in Dana
  Point, California,adopted new clinical classification.
GROUP 1. PULMONAY ARTERIAL HYPERTENSION
 Key feature: Elevation in PAP with normal PCWP
  Idiopathic (IPAH)
  Heritable ( BMPR2, ALK1, endoglin , Unknown)
  Exposure to drugs or toxins
  Persistent pulmonary hypertension of the newborn
  Associated with (APAH)
  Collagen vascular disease
  Congenital heart diseases
  Portal hypertension
  HIV infection
  Schistosomiasis
  Chronic haemolytic anaemia
 GROUP 1’ Pulmonary veno-occlusive disease(PVOD) and
   pulmonary capillary haemangiomatosis
GROUP 2. Pulmonary venous
hypertension

 Key feature: Elevation in PAP with elevation in PCWP
   Includes:
 Systolic dysfunction
 Diastolic dysfunction
 Valvular disease
GROUP 3. PH ASSOCIATED WITH
HYPOXEMIC LUNG DISEASE.

Key feature: chronic hypoxia with mild elevation of
    PAP, Includes:
   Chronic obstructive lung disease
   Interstitial lung disease
   Sleep-disordered breathing
   Alveolar hypoventilation disorders
   Chronic exposure to high altitude
   Developmental abnormalities
GROUP 4. PH DUE TO CHRONIC
THROMBOEMBOLIC DISEASE

Key feature: elevation of PA pressure with
  documentation of pulmonary arterial obstruction for
  >3 months Includes:
 Chronic pulmonary thromboembolism
GROUP 5. WITH UNCLEAR AND/OR
      MULTIFACTORIAL MECHANISMS

Key feature: elevation in PAP in association with a systemic disease
  where a causal relationship is not clearly understood. Includes:
 Haematological disorders: myeloproliferativedisorder,splenectomy.
 Systemic disorders : sarcoidosis, pulmonary Langerhans cell
                        histiocytosis, neurofibromatosis, vasculitis
 Metabolic disorders: Glycogen storage disease, Gaucher disease
                         Thyroid disorders
 Others:                Tumoural obstruction, fibrosing mediastinitis
                         chronic renal failure on dialysis
PATHOLOGY OF PH

 Different pathological features characterize the diverse
  clinical PH groups.
Group 1 - PAH
 Affect the distal pulmonary arteries (<500 um of
  diameter) in particular, are characterized by
 Medial hypertrophy,
 Eccentric and concentric intimal fibrosis,
 Recanalized thrombi appearing as fibrous webs,
 Plexiform lesions
 Pulmonary veins are classically unaffected.
PATHOLOGY OF PH

Group 1’ : Includes mainly PVOD
 Which involves septal veins and pre-septal venules
  with occlusive fibrotic lesions, venous
  muscularization, capillary proliferation , pulmonary
  oedema, occult alveolar haemorrhage, lymphatic
  dilatation and lymph node enlargement.
 Distal pulmonary arteries are affected .
PATHOLOGY OF PH
Group 2 - PH due to left heart disease:
 Characterized by enlarged and thickened pulmonary
   veins, pulmonary capillary dilatation, interstitial
   oedema,alveolar haemorrhage, and lymphatic vessel
   and lymph node enlargement.
 Distal pulmonary arteries may be affected
 Group 3 - PH due to lung diseases and/or hypoxia:
 Include medial hypertrophy and intimal obstructive
   proliferation of the distal pulmonary arteries.
 A variable degree of destruction of the vascular bed in
   emphysematous or fibrotic areas may also be present.
PATHOLOGY OF PH
Group 4 -CTEPH:
 Characterized by organized thrombi tightly attached to
  medial layer in pulmonary arteries, replacing the
  normal intima.
 These may completely occlude the lumen or form
  different grades of stenosis, webs, and bands.
 Collaterals from the systemic circulation can grow.

 Group 5-PH - unclear and/or multifactorial
   mechanisms:
 Includes conditions with different pathological
   pictures
 Aetiology is unclear or multifactorial.
PATHPHYSIOLOGY OF PH
Group 1-The exact processes that initiate the pathological
  changes seen in PAH are still unknown
 The increase in PVR is related to vasoconstriction,proliferative and
  obstructive remodelling of the pulmonary vessel
  wall, inflammation, and thrombosis.
 Excessive vasoconstriction related to abnormal function or
  expression of potassium channels in the smooth muscle cells and
  endothelial dysfunction.

Group 2- the mechanisms are multiple and include
 Passive backward transmission of the pressure elevation .
 The elevation of PVR is due to an increase in vasomotor tone of
  pulmonary arteries and fixed structural obstructive remodelling
 Vasoconstrictive reflexes arising from stretch receptors in the left
  atrium and pulmonary veins, and endothelial dysfunction
PATHPHYSIOLOGY OF PH
Group 3- mechanisms include
 Hypoxic vasoconstriction, mechanical stress of
  hyperinflated lungs, inflammation and toxic effects of
  cigarette smoke.
Group 4 - Non-resolution of acute embolic masses
  which later undergo fibrosis leading to mechanical
  obstruction of pulmonary arteries
 Pulmonary thromboembolism or in situ thrombosis
  may be initiated or aggravated by abnormalities in
  either the clotting cascade, endothelial cells, or
  platelets,
Group 5- PH with unclear and/or multifactorial
  mechanisms
PULMONARY ARTERIAL HYPERTENSION
  PAH refers to a variety of diseases that include
   idiopathic PAH.
  PAH Characterized by
  presence of pre-capillary PH in the absence of other
   causes of pre-capillary PH.
  Mean PAP >25 mmHg
  PCWP< 15 mmHg .
  CO normal or reduced
MOLECULAR ABNORMALITIES IN PAH
Prostacyclin
 Prostacyclin is a potent vasodilator, inhibits platelet
   activation, and has antiproliferative properties
 Prostacyclin synthase is decreased in the pulmonary arteries in
   PAH
Endothelin-1
 Endothelin-1 (ET-1) is a potent vasoconstrictor and stimulates
   PASMC proliferation.
 Plasma levels of ET-1 are increased in PAH and clearance is
   reduced
Nitric Oxide
 Nitric oxide (NO) is a vasodilator and inhibitor of platelet
   activation and vascular smooth-muscle cell proliferation.
 Once formed, the effects of NO are largely mediated by cGMP
   which is rapidly inactivated by PDE, especially the PDE-5
   isoenzymes.
MOLECULAR ABNORMALITIES IN PAH

Serotonin (5-HT) is a vasoconstrictor and promotes PASMC
  hypertrophy and hyperplasia.
 Allelic variation in serotonin transporter present in PAH
Vasoactive intestinal peptide (VIP) has a pharmacologic
  profile similar to prostacyclins.
 Serum and lung tissue VIP levels are decreased in PAH
  patients
GENETICS OF PAH

BONE MORPHOGENETIC PROTEIN RECEPTOR 2 GENE(BMPR2)
 BMPR2 gene encodes a type 2 receptor for bone morphogenetic
  proteins, which belong to the TGF-b superfamily involved in the
  control of vascular cell proliferation
 mutations are detected in at least 70% of cases PAH occurs in a
  familial context.
 Mutations of this gene can also be detected in 11–40% of
  apparently sporadic cases.
ACTIVIN RECEPTOR-LIKE KINASE 1 AND ENDOGLIN, have been
  identified in PAH
IDIOPATHIC PAH
 IPAH corresponds to sporadic disease,without any
  familial history of PAH or known triggering factor.
 Formerly referred to as primary pulmonary
  hypertension
 1-2 cases per million
 Females>males (1.7:1)
SIGNS AND SYMPTOMS
       OF PH
SYMPTOMS

Easy fatigability, lethargy
Exertional chest discomfort
Syncope with exertion
Cough
Hemoptysis
Hoarseness of voice
SIGNS
 Increased intensity of the pulmonic component of the
  second heart sound (P2)
 Systolic ejection murmur from TR S/O Advanced Disease.
 Diastolic murmur of PI in severe PH.
 left parasternal lift or heave
 Prominent ‘a’ wave in jugular venous system.
 Signs of RV failure:
 Jugular venous distension
 Hepatomegaly
 Ascites, and/or peripheral edema
WHO CLASSIFICATION OF FUNCTIONAL STATUS OF
PATIENTS WITH PH
 Class                                   Description
   I     Patients with PH in whom there is no limitation of usual physical activity;
          ordinary physical activity does not cause increased dyspnea, fatigue,
         chest pain, or presyncope.
  II     Patients with PH who have mild limitation of physical activity. There is no
         discomfort at rest, but normal physical activity causes increased dyspnea,
         fatigue, chest pain, or presyncope.
  III    Patients with PH who have a marked limitation of physical activity. There
         is no discomfort at rest, but less than ordinary activity causes increased
         dyspnea, fatigue, chest pain, or presyncope.
  IV     Patients with PH who are unable to perform any physical activity at rest
         and who may have signs of right ventricular failure. Dyspnea and/or
         fatigues may be present at rest, and symptoms are increased by almost
         any physical activity.   Chest 2004:126 (Suppl), JACC 2004:43 (Suppl)
NATURAL HISTORY AND SURVIVAL

 Median survival 2.8 years, with 1-, 3-, and 5-year survival
    rates of 68%, 48%, and 34%, respectively.
    Functional class remains a strong predictor of survival
   The prognosis in patients with PAH associated with the
    scleroderma is worse than for IPAH.
    CHD have a better prognosis than those with IPAH
   Cause of death is usually RV failure, manifest by progressive
    hypoxemia, tachycardia, hypotension, and edema
PARAMETERS OF WORSE PROGNOSIS
IN PAH
 Presence of RV failure
 Rapid progression of symptoms
 Syncope
 WHO –FC IV
 6 MWT < 300 m
 Pericardial effusion
DIAGNOSTIC TESTS
ELECTROCARDIOGRAPHY
 ECG has sensitivity(55%) and specificity (70%)
    detecting significant PH ,may demonstrate
   Right ventricular hypertrophy or strain
   Right axis deviation
   P pulmonale due to right atrial enlargement.
   Ventricular arrhythmias are rare.
   SVT may be present in advanced stages
Electrocardiogram

Electrocardiogram
demonstrating the
 Right ventricular
  hypertrophy with
  strain
 Right axis
  deviation ,
 Increased P-wave
  amplitude in lead
  II
CHEST RADIOGRAPH


 In 90% of patients with IPAH the chest radiograph is
  abnormal.
 Findings include central pulmonary arterial
  dilatation, which contrasts with ‘pruning’ (loss) of the
  peripheral blood vessels.
 Right atrium and RV enlargement may be seen
CHEST RADIOGRAPH

   Enlargement of      
    the central
    pulmonary
    arteries with
    attenuation of
    the peripheral
    vessels

   Right ventricular
    enlargement and
    seen.
ECHOCARDIOGRAPHY
 Is performed to estimate the pulmonary artery systolic
  pressure and to assess RV size, thickness, and function.
 In addition, left ventricular systolic and diastolic
  function, and valve function, while detecting pericardial
  effusions and intracardiac shunts.
 PH may have echocardiographic signs of right ventricular
  pressure overload, including paradoxical bulging of the
  septum into the left ventricle during systole and hypertrophy
  of the right ventricular free wall.
 As the right ventricle fails, there is dilation and
  hypokinesis, septal flattening, right atrial dilation, and
  tricuspid regurgitation
ECHOCARDIOGRAPHY
 Echocardiography uses Doppler ultrasound to estimate the
  pulmonary artery systolic pressure .
 This technique takes advantage of the tricuspid
  regurgitation that usually exists.
 The maximum tricuspid regurgitant jet velocity is recorded
  and the pulmonary artery systolic pressure (PASP) is then
  calculated by Bernoulli’s equation
   PAP systolic = 4 x ( tricuspid jet velocity squared)m/s
                               + RAP
  Theoretically, calculation of mean PAP from PA systolic
  pressure is possible
   mean PAP =0.61 X PAP systolic + 2 mmHg.
 A systolic PAP greater than 40 mmHg is suggestive of PH.
ECHOCARDIOGRAPHY

A four-chamber
echocardiographic
view of a patient who
has severe PAH.
Note the massively
dilated right ventricle
(RV) and right atrium
(RA) that have
shifted the septa and
narrowed the left
ventricle (LV) and
left atrium (LA).
Representation of echocardiographic findings in
pulmonary hypertension
VENTILATION-PERFUSION SCANNING

 Is used to evaluate patients for thromboembolic disease.
 A normal V/Q scan accurately excludes chronic
  thromboembolic disease with a sensitivity of 90 to 100
  percent and a specificity of 94 to 100 percent .
 Pulmonary angiography is necessary to confirm the
  positive V/Q scan and to define the extent of disease.
PULMONARY ANGIOGRAM

Used       to      measure
circulation in the lungs and
to visualize clots in the
lung on x-rays.
PULMONARY FUNCTION TESTS

 Pulmonary function tests (PFTs) are performed to
  identify and characterize underlying lung disease
  contributing to PH.
 An obstructive pattern is suggestive of COPD,
 Restrictive disease suggests ILD, neuromuscular
  weakness, or chest wall disease.
 In most circumstances, PH should not be attributed
  to lung disease if the PFTs are only mildly abnormal.
LABORATORY TESTS
 HIV serology to screen for HIV-associated PH
 Liver function tests to screen for porto-pulmonary
    hypertension
   Antinuclear antibody (ANA)
   Thyroid function test
   NT-proBNP is the precursor of BNP in right heart failure .
   Anti-centromere antibodies in scleroderma
   Thrombophilia screening including anti-phospholipid
    antibodies, lupus anticoagulant, and anti-cardiolipin
    antibodies should be performed in CTEPH
OVERNIGHT OXIMETRY
 Nocturnal oxyhemoglobin desaturation can be
  identified by overnight oximetry in patients with
  PH —obstructive sleep apnea-hypopnea (OSAH)
  coexists .
 Polysomnography is the gold standard diagnostic
  test for OSAH.


ULTRASONOGRAPHY
 Useful in portal hypertension
EXERCISE TESTING

 Exercise testing is most commonly performed
  using the six minute walk test (6MWT)
 Provide benchmarks for disease
  severity, response to therapy, and progression.
 In addition to distance walked, dyspnoea on
  exertion and finger O2 saturation are recorded.
 Walking distances , <250 m and O2 desaturation
  10% indicate impaired prognosis in PAH.
RIGHT HEART CATHETERIZATION

 Right heart catheterization is necessary to
  confirm the diagnosis of PH .
 Accurately determine the severity of the
  hemodynamic derangements.
 PH is confirmed if the mean pulmonary artery
  pressure is greater than 25 mmHg at rest .
 RHC is required to guide therapy
 An additional benefit of RHC is that the
  presence and/or severity of a congenital or
  acquired left-to-right shunt.
VASOREACTIVITY TEST
Aim: To detect the residual properties of vasodilatation
  of small pulmonary arteries and arterioles .
 It is recommended in patients with group 1 PAH .
 This involves the administration of a short-acting
  vasodilator and then measurement of the
  hemodynamic response .
 Agents commonly used for vasoreactivity testing
  include epoprostenol, adenosine, and inhaled nitric
  oxide .
 Epoprostenol is infused at a starting rate of 1 to 2
  ng/kg per min and increased by 2 ng/kg per min
  every 5 to 10 minutes until a clinically significant fall
  in blood pressure, an increase in heart rate, or
  adverse symptoms develop .
VASOREACTIVITY TEST

 Test is positive if mPAP decreases at least 10
  mmHg and to a value less than 40 mmHg, with an
  increased or unchanged cardiac output, and a
  minimally reduced or unchanged systemic blood
  pressure.
 Patients with a positive vasoreactivity test are
  candidates for a trial of CCB therapy.
 Negative vasoreactivity test should be treated
  with an alternative agent .
COMPUTERIZED TOMOGRAPHY

 High-resolution CT provides detailed views of the
  lung parenchyma and facilitates the diagnosis of
  interstitial lung disease and emphysema.
 High-resolution CT may be very helpful where there
  is a clinical suspicion of PVOD
 Contrast CT angiography of the PA is helpful in
  determining whether there is evidence of surgically
  accessible CTEPH.
MAGNETIC RESONANCE IMAGING

 Cardiac MRI may soon supersede this as the gold standard.
 RV mass which is difficult to quantify by other methods can
  be accurately done by MRI.
 By MRI, it can be shown that right ventricle has a crescent
  shape and left ventricle has a more circular shape.
 When the right ventricle pressure is elevated quite the
  opposite happens. This can be well demonstrated by MRI.
LUNG BIOPSY

 Is reserved only in an unusual patient in whom PH is
  not thought to be the primary disease.
 In such patients, one always finds abnormalities such
  as lung infiltrates or other findings such as
  pulmonary hemangiomatosis or pulmonary
  venoocclusive disease.
ALGORITHM FOR INVESTIGATION OF SUSPECTED PH
TREATMENT OF PH
TREATMENT OF PH

 Early identification and treatment PH is generally
    suggested because advanced disease may be less
    responsive to therapy .
    Treatment begins with a baseline assessment of
    disease severity, followed by primary therapy.
    Primary therapy is directed at the underlying cause of
    the PH.
   Some patients progress to advanced therapy, which is
    therapy directed at the PH itself, rather than the
    underlying cause of the PH.
    It includes treatment with prostanoids, endothelin
    receptor antagonists, phosphodiesterase 5
    inhibitors, or, rarely, certain calcium channel blockers.
BASELINE ASSESSMENT

 The baseline severity assessment is essential because the
    response to therapy will be measured as the change from
    baseline.
   The functional significance of the PH is determined by
    measuring exercise capacity.
    From the exercise capacity, the patient's WHO functional class
    can be determined .
   Pulmonary artery systolic pressure and right ventricular
    function can be estimated by echocardiography, and then used
    to make a presumptive diagnosis of PH.
    Right heart catheterization must be performed to accurately
    measure the hemodynamic parameters and confirm that PH
    exists.
PRIMARY THERAPY
 Primary therapy refers to treatment that is directed at the
   underlying cause of the PH.
Group 1 PAH
 There are no effective primary therapies for most types ,
   advanced therapy is often needed.
Group 2 PH — Patients with group 2 PH have PH secondary to
   left heart diseases.
 Primary t/t of the underlying heart disease.
Group 3 PH — Patients with group 3 PH have PH secondary to
   various causes of hypoxemia.
 treatment of the underlying cause of hypoxemia and
   correction of the hypoxemia with supplement of oxygen
PRIMARY THERAPY

Group 4 PH — Patients with group 4 PH have PH due to
  thromboembolic occlusion .
 Anticoagulation is primary medical therapy for patients .
 Surgical thromboendarterectomy is primary surgical
  therapy for selected patients with thromboembolic
  obstruction of the proximal pulmonary arteries .
 Perioperative mortality for this procedure is less than 10
  percent
Group 5 PH — Group 5 PH is uncommon and includes PH
  with unclear multifactorial mechanisms.
 Primary therapy is directed at the underlying cause.
GENERAL MEASURES
 All groups — Several therapies should be considered in all
   patients with PH. .
 Diuretics —
 Diuretics are used to treat fluid retention due to PH .
 Should be administered with caution to avoid decreased
   cardiac output , arrhythmias induced by hypokalemia, and
   metabolic alkalosis.
Oxygen therapy —
 Oxygen the cornerstone of therapy in patients with group 3 PH.
 Oxygen is generally administered at 1 to 4 L/min and adjusted
   to maintain the oxygen saturation above 90 percent .
 Supplemental oxygen will not significantly improve the oxygen
   saturation of patients who have Eisenmenger physiology.
GENERAL MEASURES
Digoxin —
 Improves the right ventricular ejection fraction of patients
  with group 3 PH due to COPD and biventricular failure
 helps control the heart rate of patients who have SVT
  associated with RV dysfunction .
Anticoagulation —
 increased risk for intrapulmonary thrombosis and
  thromboembolism, due to sluggish pulmonary blood
  flow, dilated right heart chambers, venous stasis, and a
  sedentary lifestyle.
 indicated in patients with IPAH , hereditary PAH , drug-
  induced PAH , or group 4 PH.
 The anticoagulant of choice is warfarin.
 Goal of an INR of approximately 2.
GENERAL MEASURES

 It is recommended to avoid pregnancy
 Immunization against influenza and pneumococcal
  infection is recommended.
 Psychosocial support should be considered in
  patients with PAH.
 Epidural anaesthesia instead of general anaesthesia
  should be utilised, if possible, for elective surgery.
 Excessive physical activity that leads to distressing
  symptoms is not recommended in patients.
ADVANCED THERAPY

 Advanced therapy is directed at the PH itself, rather
  than the underlying cause of the PH.
 It includes treatment with prostanoids, endothelin
  receptor antagonists, phosphodiesterase 5
  inhibitors, or, rarely, certain calcium channel
  blockers.
 Patient selection — Advanced therapy is considered
  for patients who have evidence of persistent PH and
  a World Health Organization WHO functional class
  II, III.
THERAPY TARGETS FOR PAH
CALCIUM CHANNEL BLOCKERS(CCB)
 Patient who may benefit from CCB therapy can be identified
    acute vasodilator response test in PAH.
    The dosages used are quite high; 90–180 mg/day for nifedipine
    (up to 240 mg/day) and 240–720 mg/day for diltiazem (up to
    900 mg/day). or amlodipine, 20 mg/d
    <20% of patients respond to calcium channel blockers in the
    long term.
   Not effective in patients who are not vasoreactive.
   Patients with BMPR2 receptor mutation do not respond .
    Side effects –
    constipation, nausea, headache, rash, edema, drowsiness, dizzi
    ness, low blood pressure
PROSTACYCLIN

 The main product of arachidonic acid in the vascular
  endothelium causes relaxation of smooth muscle
 Also results in inhibition of growth of smooth muscle
  cells.
 Intravenous prostacyclin was first introduced in the
  early 1980s.
 Successfully used in the treatment of PH resulting
  from left to right shunt, portal hypertension and HIV
  infection.
EPOPROSTENOL
 Potent vasodilator ,Unstable at acidic pH, not taken orally.
 Very short half life,<6 min requires constant Iv administration
 Initial dose: 1 – 2 ng/kg/min
 Titrating in increments of 1- 2 ng/kg/min, based upon side
  effects and tolerance to reach a “plateau” between 20 – 40
  ng/kg/min
 Side effects: Flushing, headache, jaw pain with first bite of
  food, diarrhea, nausea, erythematous rash and
  musculoskeletal pain.
 Chronic IV therapy: Line related infections, catheter associated
  venous thrombosis, thrombocytopenia
 Not available in India.
TREPROSTINIL

 Stable prostacyclin analogue.
 Can be given intravenously or subcutaneously and
    Inhalation.
   Half life of 3 hours.
   Stable at room temperature
   Initially 1.25 ng/kg/min up to maximum of 22.5
    ng/kg/min.
   Side effects: Headache, diarrhea, nausea, rash, jaw
    pain, infusion site pain, erythema or induration.
ILOPROST
 Prostacyclin analogue.
 Serum half-life of 20 – 25 mins
 For functional class 3 – 4.
 Administered via nebulized
  aerosol.
 Administered 6 – 9 times a
  day, each inhalation requires
  10 – 15 mins.
 Dose: 2.5 – 5 ug, median
  inhaled dose of 30 ug/day.
 Side effects: Cough, headache
  and flushing.
BERAPROST

 First chemically stable and orally active prostacyclin
  analogue.
 Peak concentration is reached after 30 minutes and
  elimination half-life is 35 – 40 minutes after oral
  administration.
 Median dose of 80 ug PO daily.
ENDOTHELIN RECEPTOR ANTAGONISTS
 Endothelin-1 is a potent vasoconstrictor and smooth
  muscle mitogen.
 High concentrations of endothelin-1 have been
  recorded in the lungs of patients with group 1
  PAH, including scleroderma and congenital cardiac
  shunt lesions .
 Emerged as an initial therapy for group 1 PAH in the
  late 1990s.
BOSENTAN

 Nonselective endothelin receptor antagonist,
 improves hemodynamics and exercise capacity in
    patients with group 1 PAH.
   Orally active nonpeptide antagonist of both endothelin
    receptor subtypes.
   Prevents and even reverses the development of
    PH, pulmonary vascular remodelling and right ventricular
    hypertrophy.
   Initial dose of 62.5 mg bid for first 4 weeks and followed
    by target dose of 125 mg bid.
   Side effects: Hepatotoxicity and teratogenicity.
   Available in India.
SITAXSENTAN
 Selective ETA antagonist
 Has oral bioavailability and a long duration of action (t
  1/2,   5-7h) .
 Side effects: ↑ INR and PT .


AMBRISENTAN
 ETA selective antagonist
 Under research
PHOSPHODIESTERASE INHIBITORS
SILDENAFIL
 Orally administered cyclic GMP phosphodiesterase 5 (PDE5)
  inhibitors that prolong the vasodilatory effect of NO in
  group 1 PAH.
 Approved dose is 20 mg t.i.d., but the durability of effect up
  to a up-titration beyond 20 mg t.i.d. (mainly 40–80 mg
  t.i.d.) is needed quite frequently.
 Contraindicated with Nitrates and nicorandil.
 Prevent rebound pulmonary vasoconstriction
Tadalafil and vardenafil also appear to improve outcomes in
  patients with group 1 PAH.
NITRIC OXIDE
 Inhaled form.
 Acts as direct smooth muscle
  relaxant via activation of the
  guanylate cyclase system.
 Short therapeutic half life.
 Ameliorates hypoxemia and
  lowers PVR by direct pulmonary
  vasodilatation.
SURGICAL INTERVENTIONS

Balloon Atrial Septostomy
 Allow R - L shunting to increase systemic output that
 In spite of fall in the systemic arterial oxygen saturation, will
  produce an increase in systemic oxygen transport.
 Shunt at the atrial level would allow decompression of the RA and
  RV, alleviating s/s of right heart failure.
 Considered after short term failure of maximal medical therapy.
 Severe IPAH has been the main indication other include PAH
  associated with surgically corrected CHD, CTD, distal
  CTEPH, PVOD, and pulmonary capillary haemangiomatosis.
HEART / LUNG TRANSPLANTATION

 1 year survival of 70%.
 5 year survival of 50%.
 Effective therapy for patients with end stage pulmonary
  vascular disease.
Other areas of research for treatment of PH includes
 Gene therapy
 serotonin transporter
 vasoactive intestinal peptide and tyrosine kinase inhibitors.
 Angiogenic factors and stem cells .
 Imatinib
:Treatment algorithm for pulmonary
arterial hypertension
REFERENCES


 European Heart Journal (2009) 30, 2493–
    2537doi:10.1093/eur heart/ehp297
   Journal of the American College of Cardiology/Volume 53,
    Issue 17, April  28,2009.
   Harrison's Principles of Internal Medicine18 th edition .
   http://www.uptodate.com/contents/treatment-of-
    pulmonary-hypertension-in-adults
   Indian Heart Journal 6401 (2012) 60–73
SPECIFIC CONDTIONS
ASSOCIATED WITH PH
COLLAGEN TISSUE DISEASES
 Occurs commonly with the CREST syndrome .
 Often have coexistent interstitial pulmonary fibrosis.
 Fall in diffusing capacity precede the development of PH.
 Treatment is identical to that of patients with IPAH but is less
  effective.
 The treatment of the PH, not affect the natural history of the
  underlying collagen vascular disease.
 Immunosuppressive may result in clinical improvement in patients
  with PAH associated with SLE or mixed CTD
CONGENITAL SYSTEMIC TO
    PULMONAY SHUNTS
 It is common for large post-tricuspid cardiac shunts
    (e.g.VSD, PDA) less common, in pre tricuspid shunts (e.g. ASD).
    3-year survival rate of 77% compared with 35% for untreated
    IPAH.
   Prevalence of PAH in adult CHD, 5–10%.
   Secondary erythrocytosis is beneficial for adequate O2
    transport and delivery.
   Bosentan is currently approved in Europe for WHO-FC III
    Eisenmenger’s syndrome patients.
   Heart–lung or lung transplantation with heart surgery is an
    option in special cases
PORTAL HYPERTENSION
 1–2%of patients with liver disease and portal hypertension
    develop PAH.
   The pathogenesis may be related to toxic substances derived from
    the gastrointestinal tract, due to portosystemic shunts, causing
    damage to the lung endothelium.
    Another possibility is high CO state is inducing PAH.
   Epoprostenol,bosentan, and sildenafil may exert beneficial
    haemodynamic and clinical effects in patients.
   Anticoagulation is not recommended
   Significant PAH is a contraindication to liver transplantation if
    mean PAP is 35 mmHg
LV DIASTOLIC DYSFUCTION

 PH as a result of LV diastolic failure is common but often
    unrecognized .
   It can occur with or without LV systolic failure.
   The most common risk factors are hypertensive heart
    disease; coronary artery disease; and impaired LV compliance
    related to age, diabetes, obesity, and hypoxemia.
   Symptoms of orthopnea and paroxysmal nocturnal dyspnea
    are prominent.
   Many patients improve considerably if LV end-diastolic
    pressure is lowered.
MITRAL VALVE DISEASE
 Mitral stenosis and mitral regurgitation represent important
  causes of PH from reactive pulmonary vasoconstriction
  resulting in marked elevations in PAP.
 In patients with MS, corrective surgery predictably results in a
  reduction in PAP and PVR.
 Patients with MR, however, may not have as dramatic a
  response to surgery because of persistent elevations in LV end-
  diastolic pressure.
CHRONIC OBSTRUCTIVE LUNG
    DISEASE(COPD)
 COPD associated with mild PH in the advanced stages .
 Incidence of PH in COPD with at least one previous
    hospitalization for exacerbation is 20%.
    In advanced COPD, PH is highly prevalent 50% .
    Echocardiography is recommended as a screening .
   Continuous oxygen therapy relieves the pulmonary
    vasoconstriction, reverses chronic ischemia and improves survival.
    Long-term oxygen therapy is indicated if the resting arterial Po2
    remains <55 mmHg.
   vasodilators can worsen gas exchange and not used.
INTERSTITIAL LUNG DISEASE

 PH in interstitial lung disease that results from parenchymal and
    vascular remodelling .
    The prevalence of PH is between 32 and 39%.
    Coexisting hypoxemia occurs frequently and contributes to
    morbidity.
    ILD often associated with the collagen vascular diseases.
    Many patients have pulmonary fibrosis of unknown etiology.
   The pulmonary vasodilators approved for PAH have not been
    shown to be helpful.
THROMBOEMBOLIC DISEASES

 Most patients treated for acute PTE with IV heparin and oral
  warfarin do not develop chronic PH.
 Pulmonary thromboendarterectomy is an established surgical
  treatment in patients whose thrombi are accessible .
 Lifelong anticoagulation using warfarin is mandatory
 Target INR 2.0 .
SICKLE CELL DISEASE
 The etiology is multifactorial, including
  hemolysis, hypoxemia, thromboembolism, chronic high cardiac
  output, and chronic liver disease.
 Intravascular hemolysis leading to NO deficiency is hypothesized
  as a major pathogenetic mechanism for PAH in SCD.
 Prevalance 32 and mortality is 40% in 45 month gldwin etal
 Intensification of SCD–specific therapy appears to reduce the
  morbidity.
HIV INFECTION
 Pathogenesis of HIV-related PAH remains unclear
 Incidence is estimated at 1 per 200 cases.
 Treatment is less well established in comparison with other forms
  of PAH.
 Epoprostenol, inhaled iloprost may improve exercise tolerance,
  haemodynamics and symptoms
 3-year survival rate as low as 21% in the most advanced cases
  (WHO-FC III/IV)

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Pulmonary hypertension

  • 1. PULMONARY HYPERTENSION DR. ABHAY MANGE
  • 2. PULMONARY CIRCULATION  The pulmonary circulation is the vascular system that conducts blood from the right to left side of the heart through the lungs  Pulmonary arteries are very thin walled and distensible.  Pulmonary vascular resistance (PVR) is a measure of the impedance to flow in the pulmonary vasculature  PVR Depends on pulmonary artery pressure ,left atrial pressure and the cardiac output  Normal pulmonary artery pressure=25/8 mmHg  Normal mean pulmonary artery pressure=15+/-3mmHg
  • 3.
  • 4. INTRODUCTION  Pulmonary hypertension (PH) is an abnormal elevation in pulmonary artery pressure  It is a feature of advanced disease.  The pulmonary artery pressure and pulmonary vascular resistance progressively rises, leading to right heart failure and death.  Over the years, improvement in understanding the pathogenesis has resulted in the development of targeted approaches to the treatment of PH.  Survival advantage has also been shown with some of the pharmacologic agents.
  • 5. DEFINATIONS  Pulmonary hypertension (PH) is haemodynamic and pathophysiological condition defined as mean pulmonary artery pressure > 25 mmHg at rest by Right heart Catheterization(RHC).  Pulmonary arterial hypertension (PAH) is a clinical condition characterized by the presence of pre- capillary PH in absence of other causes of pre- capillary PH such as PH due to lung diseases, chronic thromboembolic PH, or other rare diseases
  • 6. HISTORY  E. Romberg, German doctor published description of autopsy, showed thickening of the pulmonary artery but no heart or lung disease.  In 1951, 39 cases were reported by Dr. D.T. Dresdale in the United States.  Between 1967 and 1973, a 10-fold increase in unexplained PH was reported in central Europe.  The rise was subsequently traced to Aminorex fumarate, an amphetamine-like drug introduced in Europe in 1965 to control appetite.
  • 7. CLASSIFICATION OF PULMONARY HYPERTENSION  First version was proposed in 1973 at the first international conference on PPH by WHO.  Second and third world meetings on PAH in 1998 and 2003, respectively.  Fourth World meet on PH held in 2008 in Dana Point, California,adopted new clinical classification.
  • 8. GROUP 1. PULMONAY ARTERIAL HYPERTENSION Key feature: Elevation in PAP with normal PCWP  Idiopathic (IPAH)  Heritable ( BMPR2, ALK1, endoglin , Unknown)  Exposure to drugs or toxins  Persistent pulmonary hypertension of the newborn  Associated with (APAH)  Collagen vascular disease  Congenital heart diseases  Portal hypertension  HIV infection  Schistosomiasis  Chronic haemolytic anaemia GROUP 1’ Pulmonary veno-occlusive disease(PVOD) and pulmonary capillary haemangiomatosis
  • 9. GROUP 2. Pulmonary venous hypertension Key feature: Elevation in PAP with elevation in PCWP Includes:  Systolic dysfunction  Diastolic dysfunction  Valvular disease
  • 10. GROUP 3. PH ASSOCIATED WITH HYPOXEMIC LUNG DISEASE. Key feature: chronic hypoxia with mild elevation of PAP, Includes:  Chronic obstructive lung disease  Interstitial lung disease  Sleep-disordered breathing  Alveolar hypoventilation disorders  Chronic exposure to high altitude  Developmental abnormalities
  • 11. GROUP 4. PH DUE TO CHRONIC THROMBOEMBOLIC DISEASE Key feature: elevation of PA pressure with documentation of pulmonary arterial obstruction for >3 months Includes:  Chronic pulmonary thromboembolism
  • 12. GROUP 5. WITH UNCLEAR AND/OR MULTIFACTORIAL MECHANISMS Key feature: elevation in PAP in association with a systemic disease where a causal relationship is not clearly understood. Includes:  Haematological disorders: myeloproliferativedisorder,splenectomy.  Systemic disorders : sarcoidosis, pulmonary Langerhans cell histiocytosis, neurofibromatosis, vasculitis  Metabolic disorders: Glycogen storage disease, Gaucher disease Thyroid disorders  Others: Tumoural obstruction, fibrosing mediastinitis chronic renal failure on dialysis
  • 13. PATHOLOGY OF PH  Different pathological features characterize the diverse clinical PH groups. Group 1 - PAH  Affect the distal pulmonary arteries (<500 um of diameter) in particular, are characterized by  Medial hypertrophy,  Eccentric and concentric intimal fibrosis,  Recanalized thrombi appearing as fibrous webs,  Plexiform lesions  Pulmonary veins are classically unaffected.
  • 14.
  • 15. PATHOLOGY OF PH Group 1’ : Includes mainly PVOD  Which involves septal veins and pre-septal venules with occlusive fibrotic lesions, venous muscularization, capillary proliferation , pulmonary oedema, occult alveolar haemorrhage, lymphatic dilatation and lymph node enlargement.  Distal pulmonary arteries are affected .
  • 16. PATHOLOGY OF PH Group 2 - PH due to left heart disease:  Characterized by enlarged and thickened pulmonary veins, pulmonary capillary dilatation, interstitial oedema,alveolar haemorrhage, and lymphatic vessel and lymph node enlargement.  Distal pulmonary arteries may be affected Group 3 - PH due to lung diseases and/or hypoxia:  Include medial hypertrophy and intimal obstructive proliferation of the distal pulmonary arteries.  A variable degree of destruction of the vascular bed in emphysematous or fibrotic areas may also be present.
  • 17. PATHOLOGY OF PH Group 4 -CTEPH:  Characterized by organized thrombi tightly attached to medial layer in pulmonary arteries, replacing the normal intima.  These may completely occlude the lumen or form different grades of stenosis, webs, and bands.  Collaterals from the systemic circulation can grow. Group 5-PH - unclear and/or multifactorial mechanisms:  Includes conditions with different pathological pictures  Aetiology is unclear or multifactorial.
  • 18. PATHPHYSIOLOGY OF PH Group 1-The exact processes that initiate the pathological changes seen in PAH are still unknown  The increase in PVR is related to vasoconstriction,proliferative and obstructive remodelling of the pulmonary vessel wall, inflammation, and thrombosis.  Excessive vasoconstriction related to abnormal function or expression of potassium channels in the smooth muscle cells and endothelial dysfunction. Group 2- the mechanisms are multiple and include  Passive backward transmission of the pressure elevation .  The elevation of PVR is due to an increase in vasomotor tone of pulmonary arteries and fixed structural obstructive remodelling  Vasoconstrictive reflexes arising from stretch receptors in the left atrium and pulmonary veins, and endothelial dysfunction
  • 19. PATHPHYSIOLOGY OF PH Group 3- mechanisms include  Hypoxic vasoconstriction, mechanical stress of hyperinflated lungs, inflammation and toxic effects of cigarette smoke. Group 4 - Non-resolution of acute embolic masses which later undergo fibrosis leading to mechanical obstruction of pulmonary arteries  Pulmonary thromboembolism or in situ thrombosis may be initiated or aggravated by abnormalities in either the clotting cascade, endothelial cells, or platelets, Group 5- PH with unclear and/or multifactorial mechanisms
  • 20. PULMONARY ARTERIAL HYPERTENSION  PAH refers to a variety of diseases that include idiopathic PAH.  PAH Characterized by  presence of pre-capillary PH in the absence of other causes of pre-capillary PH.  Mean PAP >25 mmHg  PCWP< 15 mmHg .  CO normal or reduced
  • 21. MOLECULAR ABNORMALITIES IN PAH Prostacyclin  Prostacyclin is a potent vasodilator, inhibits platelet activation, and has antiproliferative properties  Prostacyclin synthase is decreased in the pulmonary arteries in PAH Endothelin-1  Endothelin-1 (ET-1) is a potent vasoconstrictor and stimulates PASMC proliferation.  Plasma levels of ET-1 are increased in PAH and clearance is reduced Nitric Oxide  Nitric oxide (NO) is a vasodilator and inhibitor of platelet activation and vascular smooth-muscle cell proliferation.  Once formed, the effects of NO are largely mediated by cGMP which is rapidly inactivated by PDE, especially the PDE-5 isoenzymes.
  • 22. MOLECULAR ABNORMALITIES IN PAH Serotonin (5-HT) is a vasoconstrictor and promotes PASMC hypertrophy and hyperplasia.  Allelic variation in serotonin transporter present in PAH Vasoactive intestinal peptide (VIP) has a pharmacologic profile similar to prostacyclins.  Serum and lung tissue VIP levels are decreased in PAH patients
  • 23. GENETICS OF PAH BONE MORPHOGENETIC PROTEIN RECEPTOR 2 GENE(BMPR2)  BMPR2 gene encodes a type 2 receptor for bone morphogenetic proteins, which belong to the TGF-b superfamily involved in the control of vascular cell proliferation  mutations are detected in at least 70% of cases PAH occurs in a familial context.  Mutations of this gene can also be detected in 11–40% of apparently sporadic cases. ACTIVIN RECEPTOR-LIKE KINASE 1 AND ENDOGLIN, have been identified in PAH
  • 24. IDIOPATHIC PAH  IPAH corresponds to sporadic disease,without any familial history of PAH or known triggering factor.  Formerly referred to as primary pulmonary hypertension  1-2 cases per million  Females>males (1.7:1)
  • 26. SYMPTOMS Easy fatigability, lethargy Exertional chest discomfort Syncope with exertion Cough Hemoptysis Hoarseness of voice
  • 27. SIGNS  Increased intensity of the pulmonic component of the second heart sound (P2)  Systolic ejection murmur from TR S/O Advanced Disease.  Diastolic murmur of PI in severe PH.  left parasternal lift or heave  Prominent ‘a’ wave in jugular venous system.  Signs of RV failure:  Jugular venous distension  Hepatomegaly  Ascites, and/or peripheral edema
  • 28. WHO CLASSIFICATION OF FUNCTIONAL STATUS OF PATIENTS WITH PH Class Description I Patients with PH in whom there is no limitation of usual physical activity; ordinary physical activity does not cause increased dyspnea, fatigue, chest pain, or presyncope. II Patients with PH who have mild limitation of physical activity. There is no discomfort at rest, but normal physical activity causes increased dyspnea, fatigue, chest pain, or presyncope. III Patients with PH who have a marked limitation of physical activity. There is no discomfort at rest, but less than ordinary activity causes increased dyspnea, fatigue, chest pain, or presyncope. IV Patients with PH who are unable to perform any physical activity at rest and who may have signs of right ventricular failure. Dyspnea and/or fatigues may be present at rest, and symptoms are increased by almost any physical activity. Chest 2004:126 (Suppl), JACC 2004:43 (Suppl)
  • 29. NATURAL HISTORY AND SURVIVAL  Median survival 2.8 years, with 1-, 3-, and 5-year survival rates of 68%, 48%, and 34%, respectively.  Functional class remains a strong predictor of survival  The prognosis in patients with PAH associated with the scleroderma is worse than for IPAH.  CHD have a better prognosis than those with IPAH  Cause of death is usually RV failure, manifest by progressive hypoxemia, tachycardia, hypotension, and edema
  • 30. PARAMETERS OF WORSE PROGNOSIS IN PAH  Presence of RV failure  Rapid progression of symptoms  Syncope  WHO –FC IV  6 MWT < 300 m  Pericardial effusion
  • 32. ELECTROCARDIOGRAPHY  ECG has sensitivity(55%) and specificity (70%) detecting significant PH ,may demonstrate  Right ventricular hypertrophy or strain  Right axis deviation  P pulmonale due to right atrial enlargement.  Ventricular arrhythmias are rare.  SVT may be present in advanced stages
  • 33. Electrocardiogram Electrocardiogram demonstrating the  Right ventricular hypertrophy with strain  Right axis deviation ,  Increased P-wave amplitude in lead II
  • 34. CHEST RADIOGRAPH  In 90% of patients with IPAH the chest radiograph is abnormal.  Findings include central pulmonary arterial dilatation, which contrasts with ‘pruning’ (loss) of the peripheral blood vessels.  Right atrium and RV enlargement may be seen
  • 35. CHEST RADIOGRAPH  Enlargement of  the central pulmonary arteries with attenuation of the peripheral vessels  Right ventricular enlargement and seen.
  • 36. ECHOCARDIOGRAPHY  Is performed to estimate the pulmonary artery systolic pressure and to assess RV size, thickness, and function.  In addition, left ventricular systolic and diastolic function, and valve function, while detecting pericardial effusions and intracardiac shunts.  PH may have echocardiographic signs of right ventricular pressure overload, including paradoxical bulging of the septum into the left ventricle during systole and hypertrophy of the right ventricular free wall.  As the right ventricle fails, there is dilation and hypokinesis, septal flattening, right atrial dilation, and tricuspid regurgitation
  • 37. ECHOCARDIOGRAPHY  Echocardiography uses Doppler ultrasound to estimate the pulmonary artery systolic pressure .  This technique takes advantage of the tricuspid regurgitation that usually exists.  The maximum tricuspid regurgitant jet velocity is recorded and the pulmonary artery systolic pressure (PASP) is then calculated by Bernoulli’s equation PAP systolic = 4 x ( tricuspid jet velocity squared)m/s + RAP Theoretically, calculation of mean PAP from PA systolic pressure is possible mean PAP =0.61 X PAP systolic + 2 mmHg.  A systolic PAP greater than 40 mmHg is suggestive of PH.
  • 38. ECHOCARDIOGRAPHY A four-chamber echocardiographic view of a patient who has severe PAH. Note the massively dilated right ventricle (RV) and right atrium (RA) that have shifted the septa and narrowed the left ventricle (LV) and left atrium (LA).
  • 39. Representation of echocardiographic findings in pulmonary hypertension
  • 40. VENTILATION-PERFUSION SCANNING  Is used to evaluate patients for thromboembolic disease.  A normal V/Q scan accurately excludes chronic thromboembolic disease with a sensitivity of 90 to 100 percent and a specificity of 94 to 100 percent .  Pulmonary angiography is necessary to confirm the positive V/Q scan and to define the extent of disease.
  • 41. PULMONARY ANGIOGRAM Used to measure circulation in the lungs and to visualize clots in the lung on x-rays.
  • 42. PULMONARY FUNCTION TESTS  Pulmonary function tests (PFTs) are performed to identify and characterize underlying lung disease contributing to PH.  An obstructive pattern is suggestive of COPD,  Restrictive disease suggests ILD, neuromuscular weakness, or chest wall disease.  In most circumstances, PH should not be attributed to lung disease if the PFTs are only mildly abnormal.
  • 43. LABORATORY TESTS  HIV serology to screen for HIV-associated PH  Liver function tests to screen for porto-pulmonary hypertension  Antinuclear antibody (ANA)  Thyroid function test  NT-proBNP is the precursor of BNP in right heart failure .  Anti-centromere antibodies in scleroderma  Thrombophilia screening including anti-phospholipid antibodies, lupus anticoagulant, and anti-cardiolipin antibodies should be performed in CTEPH
  • 44. OVERNIGHT OXIMETRY  Nocturnal oxyhemoglobin desaturation can be identified by overnight oximetry in patients with PH —obstructive sleep apnea-hypopnea (OSAH) coexists .  Polysomnography is the gold standard diagnostic test for OSAH. ULTRASONOGRAPHY  Useful in portal hypertension
  • 45. EXERCISE TESTING  Exercise testing is most commonly performed using the six minute walk test (6MWT)  Provide benchmarks for disease severity, response to therapy, and progression.  In addition to distance walked, dyspnoea on exertion and finger O2 saturation are recorded.  Walking distances , <250 m and O2 desaturation 10% indicate impaired prognosis in PAH.
  • 46. RIGHT HEART CATHETERIZATION  Right heart catheterization is necessary to confirm the diagnosis of PH .  Accurately determine the severity of the hemodynamic derangements.  PH is confirmed if the mean pulmonary artery pressure is greater than 25 mmHg at rest .  RHC is required to guide therapy  An additional benefit of RHC is that the presence and/or severity of a congenital or acquired left-to-right shunt.
  • 47. VASOREACTIVITY TEST Aim: To detect the residual properties of vasodilatation of small pulmonary arteries and arterioles .  It is recommended in patients with group 1 PAH .  This involves the administration of a short-acting vasodilator and then measurement of the hemodynamic response .  Agents commonly used for vasoreactivity testing include epoprostenol, adenosine, and inhaled nitric oxide .  Epoprostenol is infused at a starting rate of 1 to 2 ng/kg per min and increased by 2 ng/kg per min every 5 to 10 minutes until a clinically significant fall in blood pressure, an increase in heart rate, or adverse symptoms develop .
  • 48. VASOREACTIVITY TEST  Test is positive if mPAP decreases at least 10 mmHg and to a value less than 40 mmHg, with an increased or unchanged cardiac output, and a minimally reduced or unchanged systemic blood pressure.  Patients with a positive vasoreactivity test are candidates for a trial of CCB therapy.  Negative vasoreactivity test should be treated with an alternative agent .
  • 49. COMPUTERIZED TOMOGRAPHY  High-resolution CT provides detailed views of the lung parenchyma and facilitates the diagnosis of interstitial lung disease and emphysema.  High-resolution CT may be very helpful where there is a clinical suspicion of PVOD  Contrast CT angiography of the PA is helpful in determining whether there is evidence of surgically accessible CTEPH.
  • 50. MAGNETIC RESONANCE IMAGING  Cardiac MRI may soon supersede this as the gold standard.  RV mass which is difficult to quantify by other methods can be accurately done by MRI.  By MRI, it can be shown that right ventricle has a crescent shape and left ventricle has a more circular shape.  When the right ventricle pressure is elevated quite the opposite happens. This can be well demonstrated by MRI.
  • 51. LUNG BIOPSY  Is reserved only in an unusual patient in whom PH is not thought to be the primary disease.  In such patients, one always finds abnormalities such as lung infiltrates or other findings such as pulmonary hemangiomatosis or pulmonary venoocclusive disease.
  • 52. ALGORITHM FOR INVESTIGATION OF SUSPECTED PH
  • 54. TREATMENT OF PH  Early identification and treatment PH is generally suggested because advanced disease may be less responsive to therapy .  Treatment begins with a baseline assessment of disease severity, followed by primary therapy.  Primary therapy is directed at the underlying cause of the PH.  Some patients progress to advanced therapy, which is therapy directed at the PH itself, rather than the underlying cause of the PH.  It includes treatment with prostanoids, endothelin receptor antagonists, phosphodiesterase 5 inhibitors, or, rarely, certain calcium channel blockers.
  • 55. BASELINE ASSESSMENT  The baseline severity assessment is essential because the response to therapy will be measured as the change from baseline.  The functional significance of the PH is determined by measuring exercise capacity.  From the exercise capacity, the patient's WHO functional class can be determined .  Pulmonary artery systolic pressure and right ventricular function can be estimated by echocardiography, and then used to make a presumptive diagnosis of PH.  Right heart catheterization must be performed to accurately measure the hemodynamic parameters and confirm that PH exists.
  • 56. PRIMARY THERAPY Primary therapy refers to treatment that is directed at the underlying cause of the PH. Group 1 PAH  There are no effective primary therapies for most types , advanced therapy is often needed. Group 2 PH — Patients with group 2 PH have PH secondary to left heart diseases.  Primary t/t of the underlying heart disease. Group 3 PH — Patients with group 3 PH have PH secondary to various causes of hypoxemia.  treatment of the underlying cause of hypoxemia and correction of the hypoxemia with supplement of oxygen
  • 57. PRIMARY THERAPY Group 4 PH — Patients with group 4 PH have PH due to thromboembolic occlusion .  Anticoagulation is primary medical therapy for patients .  Surgical thromboendarterectomy is primary surgical therapy for selected patients with thromboembolic obstruction of the proximal pulmonary arteries .  Perioperative mortality for this procedure is less than 10 percent Group 5 PH — Group 5 PH is uncommon and includes PH with unclear multifactorial mechanisms.  Primary therapy is directed at the underlying cause.
  • 58. GENERAL MEASURES  All groups — Several therapies should be considered in all patients with PH. . Diuretics —  Diuretics are used to treat fluid retention due to PH .  Should be administered with caution to avoid decreased cardiac output , arrhythmias induced by hypokalemia, and metabolic alkalosis. Oxygen therapy —  Oxygen the cornerstone of therapy in patients with group 3 PH.  Oxygen is generally administered at 1 to 4 L/min and adjusted to maintain the oxygen saturation above 90 percent .  Supplemental oxygen will not significantly improve the oxygen saturation of patients who have Eisenmenger physiology.
  • 59. GENERAL MEASURES Digoxin —  Improves the right ventricular ejection fraction of patients with group 3 PH due to COPD and biventricular failure  helps control the heart rate of patients who have SVT associated with RV dysfunction . Anticoagulation —  increased risk for intrapulmonary thrombosis and thromboembolism, due to sluggish pulmonary blood flow, dilated right heart chambers, venous stasis, and a sedentary lifestyle.  indicated in patients with IPAH , hereditary PAH , drug- induced PAH , or group 4 PH.  The anticoagulant of choice is warfarin.  Goal of an INR of approximately 2.
  • 60. GENERAL MEASURES  It is recommended to avoid pregnancy  Immunization against influenza and pneumococcal infection is recommended.  Psychosocial support should be considered in patients with PAH.  Epidural anaesthesia instead of general anaesthesia should be utilised, if possible, for elective surgery.  Excessive physical activity that leads to distressing symptoms is not recommended in patients.
  • 61. ADVANCED THERAPY  Advanced therapy is directed at the PH itself, rather than the underlying cause of the PH.  It includes treatment with prostanoids, endothelin receptor antagonists, phosphodiesterase 5 inhibitors, or, rarely, certain calcium channel blockers.  Patient selection — Advanced therapy is considered for patients who have evidence of persistent PH and a World Health Organization WHO functional class II, III.
  • 63. CALCIUM CHANNEL BLOCKERS(CCB)  Patient who may benefit from CCB therapy can be identified acute vasodilator response test in PAH.  The dosages used are quite high; 90–180 mg/day for nifedipine (up to 240 mg/day) and 240–720 mg/day for diltiazem (up to 900 mg/day). or amlodipine, 20 mg/d  <20% of patients respond to calcium channel blockers in the long term.  Not effective in patients who are not vasoreactive.  Patients with BMPR2 receptor mutation do not respond .  Side effects – constipation, nausea, headache, rash, edema, drowsiness, dizzi ness, low blood pressure
  • 64. PROSTACYCLIN  The main product of arachidonic acid in the vascular endothelium causes relaxation of smooth muscle  Also results in inhibition of growth of smooth muscle cells.  Intravenous prostacyclin was first introduced in the early 1980s.  Successfully used in the treatment of PH resulting from left to right shunt, portal hypertension and HIV infection.
  • 65. EPOPROSTENOL  Potent vasodilator ,Unstable at acidic pH, not taken orally.  Very short half life,<6 min requires constant Iv administration  Initial dose: 1 – 2 ng/kg/min  Titrating in increments of 1- 2 ng/kg/min, based upon side effects and tolerance to reach a “plateau” between 20 – 40 ng/kg/min  Side effects: Flushing, headache, jaw pain with first bite of food, diarrhea, nausea, erythematous rash and musculoskeletal pain.  Chronic IV therapy: Line related infections, catheter associated venous thrombosis, thrombocytopenia  Not available in India.
  • 66.
  • 67. TREPROSTINIL  Stable prostacyclin analogue.  Can be given intravenously or subcutaneously and Inhalation.  Half life of 3 hours.  Stable at room temperature  Initially 1.25 ng/kg/min up to maximum of 22.5 ng/kg/min.  Side effects: Headache, diarrhea, nausea, rash, jaw pain, infusion site pain, erythema or induration.
  • 68.
  • 69. ILOPROST  Prostacyclin analogue.  Serum half-life of 20 – 25 mins  For functional class 3 – 4.  Administered via nebulized aerosol.  Administered 6 – 9 times a day, each inhalation requires 10 – 15 mins.  Dose: 2.5 – 5 ug, median inhaled dose of 30 ug/day.  Side effects: Cough, headache and flushing.
  • 70. BERAPROST  First chemically stable and orally active prostacyclin analogue.  Peak concentration is reached after 30 minutes and elimination half-life is 35 – 40 minutes after oral administration.  Median dose of 80 ug PO daily.
  • 71. ENDOTHELIN RECEPTOR ANTAGONISTS  Endothelin-1 is a potent vasoconstrictor and smooth muscle mitogen.  High concentrations of endothelin-1 have been recorded in the lungs of patients with group 1 PAH, including scleroderma and congenital cardiac shunt lesions .  Emerged as an initial therapy for group 1 PAH in the late 1990s.
  • 72. BOSENTAN  Nonselective endothelin receptor antagonist,  improves hemodynamics and exercise capacity in patients with group 1 PAH.  Orally active nonpeptide antagonist of both endothelin receptor subtypes.  Prevents and even reverses the development of PH, pulmonary vascular remodelling and right ventricular hypertrophy.  Initial dose of 62.5 mg bid for first 4 weeks and followed by target dose of 125 mg bid.  Side effects: Hepatotoxicity and teratogenicity.  Available in India.
  • 73. SITAXSENTAN  Selective ETA antagonist  Has oral bioavailability and a long duration of action (t 1/2, 5-7h) .  Side effects: ↑ INR and PT . AMBRISENTAN  ETA selective antagonist  Under research
  • 74. PHOSPHODIESTERASE INHIBITORS SILDENAFIL  Orally administered cyclic GMP phosphodiesterase 5 (PDE5) inhibitors that prolong the vasodilatory effect of NO in group 1 PAH.  Approved dose is 20 mg t.i.d., but the durability of effect up to a up-titration beyond 20 mg t.i.d. (mainly 40–80 mg t.i.d.) is needed quite frequently.  Contraindicated with Nitrates and nicorandil.  Prevent rebound pulmonary vasoconstriction Tadalafil and vardenafil also appear to improve outcomes in patients with group 1 PAH.
  • 75. NITRIC OXIDE  Inhaled form.  Acts as direct smooth muscle relaxant via activation of the guanylate cyclase system.  Short therapeutic half life.  Ameliorates hypoxemia and lowers PVR by direct pulmonary vasodilatation.
  • 76. SURGICAL INTERVENTIONS Balloon Atrial Septostomy  Allow R - L shunting to increase systemic output that  In spite of fall in the systemic arterial oxygen saturation, will produce an increase in systemic oxygen transport.  Shunt at the atrial level would allow decompression of the RA and RV, alleviating s/s of right heart failure.  Considered after short term failure of maximal medical therapy.  Severe IPAH has been the main indication other include PAH associated with surgically corrected CHD, CTD, distal CTEPH, PVOD, and pulmonary capillary haemangiomatosis.
  • 77. HEART / LUNG TRANSPLANTATION  1 year survival of 70%.  5 year survival of 50%.  Effective therapy for patients with end stage pulmonary vascular disease. Other areas of research for treatment of PH includes  Gene therapy  serotonin transporter  vasoactive intestinal peptide and tyrosine kinase inhibitors.  Angiogenic factors and stem cells .  Imatinib
  • 78. :Treatment algorithm for pulmonary arterial hypertension
  • 79. REFERENCES  European Heart Journal (2009) 30, 2493– 2537doi:10.1093/eur heart/ehp297  Journal of the American College of Cardiology/Volume 53, Issue 17, April  28,2009.  Harrison's Principles of Internal Medicine18 th edition .  http://www.uptodate.com/contents/treatment-of- pulmonary-hypertension-in-adults  Indian Heart Journal 6401 (2012) 60–73
  • 81. COLLAGEN TISSUE DISEASES  Occurs commonly with the CREST syndrome .  Often have coexistent interstitial pulmonary fibrosis.  Fall in diffusing capacity precede the development of PH.  Treatment is identical to that of patients with IPAH but is less effective.  The treatment of the PH, not affect the natural history of the underlying collagen vascular disease.  Immunosuppressive may result in clinical improvement in patients with PAH associated with SLE or mixed CTD
  • 82. CONGENITAL SYSTEMIC TO PULMONAY SHUNTS  It is common for large post-tricuspid cardiac shunts (e.g.VSD, PDA) less common, in pre tricuspid shunts (e.g. ASD).  3-year survival rate of 77% compared with 35% for untreated IPAH.  Prevalence of PAH in adult CHD, 5–10%.  Secondary erythrocytosis is beneficial for adequate O2 transport and delivery.  Bosentan is currently approved in Europe for WHO-FC III Eisenmenger’s syndrome patients.  Heart–lung or lung transplantation with heart surgery is an option in special cases
  • 83. PORTAL HYPERTENSION  1–2%of patients with liver disease and portal hypertension develop PAH.  The pathogenesis may be related to toxic substances derived from the gastrointestinal tract, due to portosystemic shunts, causing damage to the lung endothelium.  Another possibility is high CO state is inducing PAH.  Epoprostenol,bosentan, and sildenafil may exert beneficial haemodynamic and clinical effects in patients.  Anticoagulation is not recommended  Significant PAH is a contraindication to liver transplantation if mean PAP is 35 mmHg
  • 84. LV DIASTOLIC DYSFUCTION  PH as a result of LV diastolic failure is common but often unrecognized .  It can occur with or without LV systolic failure.  The most common risk factors are hypertensive heart disease; coronary artery disease; and impaired LV compliance related to age, diabetes, obesity, and hypoxemia.  Symptoms of orthopnea and paroxysmal nocturnal dyspnea are prominent.  Many patients improve considerably if LV end-diastolic pressure is lowered.
  • 85. MITRAL VALVE DISEASE  Mitral stenosis and mitral regurgitation represent important causes of PH from reactive pulmonary vasoconstriction resulting in marked elevations in PAP.  In patients with MS, corrective surgery predictably results in a reduction in PAP and PVR.  Patients with MR, however, may not have as dramatic a response to surgery because of persistent elevations in LV end- diastolic pressure.
  • 86. CHRONIC OBSTRUCTIVE LUNG DISEASE(COPD)  COPD associated with mild PH in the advanced stages .  Incidence of PH in COPD with at least one previous hospitalization for exacerbation is 20%.  In advanced COPD, PH is highly prevalent 50% .  Echocardiography is recommended as a screening .  Continuous oxygen therapy relieves the pulmonary vasoconstriction, reverses chronic ischemia and improves survival.  Long-term oxygen therapy is indicated if the resting arterial Po2 remains <55 mmHg.  vasodilators can worsen gas exchange and not used.
  • 87. INTERSTITIAL LUNG DISEASE  PH in interstitial lung disease that results from parenchymal and vascular remodelling .  The prevalence of PH is between 32 and 39%.  Coexisting hypoxemia occurs frequently and contributes to morbidity.  ILD often associated with the collagen vascular diseases.  Many patients have pulmonary fibrosis of unknown etiology.  The pulmonary vasodilators approved for PAH have not been shown to be helpful.
  • 88. THROMBOEMBOLIC DISEASES  Most patients treated for acute PTE with IV heparin and oral warfarin do not develop chronic PH.  Pulmonary thromboendarterectomy is an established surgical treatment in patients whose thrombi are accessible .  Lifelong anticoagulation using warfarin is mandatory  Target INR 2.0 .
  • 89. SICKLE CELL DISEASE  The etiology is multifactorial, including hemolysis, hypoxemia, thromboembolism, chronic high cardiac output, and chronic liver disease.  Intravascular hemolysis leading to NO deficiency is hypothesized as a major pathogenetic mechanism for PAH in SCD.  Prevalance 32 and mortality is 40% in 45 month gldwin etal  Intensification of SCD–specific therapy appears to reduce the morbidity.
  • 90. HIV INFECTION  Pathogenesis of HIV-related PAH remains unclear  Incidence is estimated at 1 per 200 cases.  Treatment is less well established in comparison with other forms of PAH.  Epoprostenol, inhaled iloprost may improve exercise tolerance, haemodynamics and symptoms  3-year survival rate as low as 21% in the most advanced cases (WHO-FC III/IV)